Human metapneumovirus (HMPV), although only recently discovered, has rapidly become recognized globally as a major respiratory pathogen in young children, the elderly and immunocompromised individuals. It is closely related to human respiratory syncytial virus (HRSV), and produces an analogous clinical syndrome in infected individuals. In this highly focused application, we propose to thoroughly characterize the human antibody response against HMPV by recovering an extensive panel of over 50 monoclonal antibodies elicited in different individuals as a result of natural infection with this pathogen. Studies will be directed to antibodies recognizing the fusion (F) protein of the virus, which is largely invariant between heterologous virus strains, is highly immunogenic and is the target of neutralizing antibody responses. Using this human monoclonal antibody panel, we will map antigenically the HMPV F protein and identify antibodies with exceptional virus neutralizing properties that are able to protect rodents from virus challenge and are well positioned for immediate clinical development as passive prophylactic agents for the prevention of HMPV disease in vulnerable patient cohorts. The neutralization potency of selected antibodies will be further improved in vitro with the aim of enhancing their potential clinical efficacy in protecting from HMPV infections. The proposed grant as four aims. (1) To recover an expansive panel of human monoclonal antibodies against the HMPV fusion (F) protein, (2) To determine the neutralization potency of the monoclonal antibodies against HMPV in vitro and in vivo, (3) To evolve ultra-potent HMPV neutralizing antibodies from the naturally occurring antibodies we first recover. PUBLIC HEALTH RELEVANCE: Human metapneumovirus (HMPV), although only recently discovered, has rapidly become recognized globally as a major respiratory pathogen in young children, the elderly and immunocompromised individuals. In this program, we propose to thoroughly characterize the human antibody response against the fusion (F) protein of the virus. The F protein is largely invariant between heterologous virus strains, is highly immunogenic, and is the target of neutralizing antibody responses. Human antibodies with exceptional HMPV neutralizing properties and that protect rodents from virus challenge will be identified and evolved. Such antibodies will be positioned for immediate clinical development as passive prophylactic agents for the prevention of HMPV disease in vulnerable patient cohorts.